Circulating tumor DNA (ctDNA) has emerged as a promising biomarker in colorectal cancer, offering dynamic insight into disease burden and recurrence risk. However, questions remain about its clinical utility and optimal application, as well as its equitable access across practice settings. At the 2025 Summit on Cancer Health Disparities in Seattle, Stacey Cohen, MD, reviewed the current evidence supporting ctDNA-based risk stratification and surveillance in colorectal cancer.

"Because ctDNA has a short half-life—just a few hours—it gives us a near real-time snapshot of disease activity."

— STACEY COHEN, MD

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“New technologies often debut in academic centers,” said Dr. Cohen, Associate Professor of the Clinical Research Division at Fred Hutchinson Cancer Center and Associate Professor in the Division of Hematology/Oncology at the University of Washington in Seattle. “So, the challenge is how we disseminate and implement them effectively in diverse care environments.”

A Real-Time Biomarker

Dr. Cohen began with a biological overview of ctDNA, a tumor-derived component of cell-free DNA that can be identified and quantified based on mutation profiles and fragment characteristics. “Because ctDNA has a short half-life—just a few hours—it gives us a near real-time snapshot of disease activity,” she noted. This makes ctDNA an appealing biomarker for tracking molecular residual disease, monitoring treatment response, and identifying early relapse.

Colorectal cancer is particularly amenable to ctDNA applications, given its relatively high rate of DNA shedding and common metastatic spread to other high-shedding organs such as the liver. However, variability in tumor shedding limits the broader applicability of ctDNA across different cancer types and metastatic sites, she cautioned.

Tumor-Informed vs Tumor-Uninformed Testing Approaches

Dr. Cohen described two major approaches to ctDNA testing: tumor-informed and tumor-uninformed. The former involves sequencing a patient’s tumor to identify specific mutations, which are then tracked in the blood. The latter approach uses a broad, predefined mutation panel that does not rely on sequencing the individual patient’s tumor tissue.

“Tumor-informed assays may offer higher sensitivity,” she said. “However, turnaround times are longer—up to 4 to 6 weeks—due to the requirement for tumor sequencing.” In contrast, tumor-uninformed platforms can yield results within 7 to 14 days but may lack the same degree of specificity.

Retrospective Data Support Prognostic Value

Numerous retrospective studies have demonstrated that postoperative ctDNA status strongly correlates with recurrence risk. “Broadly speaking, patients who are ctDNA-negative after surgery seem to do way better than patients who are ctDNA-positive,” Dr. Cohen said. “We see very big differences between patients who are ctDNA-negative and ctDNA-positive.”

These findings suggest a potential role for ctDNA in guiding surveillance intensity or even adjuvant therapy decisions. However, the absence of prospective, practice-defining data has limited its routine adoption.

Prospective Insights: DYNAMIC Trial

Dr. Cohen discussed the DYNAMIC trial, a prospective, randomized study evaluating ctDNA-guided therapy for stage II colon cancer.¹ Participants were assigned to standard management or a ctDNA-guided arm, where adjuvant chemotherapy was reserved for those who tested ctDNA-positive at 4 and/or 7 weeks postoperatively.

Chemotherapy use was significantly reduced in the ctDNA-guided group (15%) compared with the group that received standard management (28%), without compromising recurrence-free survival at 2 years. However, treatment intensity differed: Oxaliplatin-based regimens were more common in the ctDNA-guided arm, potentially confounding outcomes.

“This is why it’s not practice-changing at this time,” Dr. Cohen said. “But it really tested our idea that we know best who needs chemotherapy—or maybe that we know best who does not need chemotherapy.”

Expanding the Evidence Base: CIRCULATE-North America

In stage III colon cancer, where adjuvant chemotherapy is the current standard of care, the CIRCULATE-North America trial is evaluating whether ctDNA status can inform treatment intensity.² Specifically, it aims to determine whether ctDNA-negative patients can safely avoid chemotherapy, whereas ctDNA-positive patients may benefit from escalation of therapy.

“This is testing a big de-escalation question in ctDNA-negative patients,” Dr. Cohen explained, “and an escalation question in those who are ctDNA-positive.” The results may help to refine treatment strategies by integrating molecular and clinicopathologic risk factors.

Longitudinal Monitoring and Lead Time Advantage

Beyond single time-point testing, longitudinal ctDNA surveillance has been explored in large observational cohorts such as GALAXY, BESPOKE, and INTERCEPT.^3-5 Patients who remain ctDNA-negative over time consistently demonstrate excellent outcomes, whereas those who remain or have ever been ctDNA-positive—even if they later convert to ctDNA-negative—continue to face an elevated risk of recurrence.

Dr. Cohen noted that in the INTERCEPT study, the median lead time from ctDNA detection to radiographic evidence of disease was approximately 5.5 months for those ctDNA-positive patients without an immediately detectable recurrence. This finding suggests that ctDNA may provide an early warning signal, often preceding visible recurrence by several months. “That helps us understand how to frame this to patients,” she said, adding that clinicians may need to prepare patients for an extended period of uncertainty when imaging remains negative despite molecular evidence of disease.

Utility Beyond Detection: Implications for Management

In some cases, positive ctDNA findings have prompted additional imaging and, when actionable disease is identified, localized therapies such as metastasectomy. However, the broader impact on overall survival remains uncertain.

“The hope is that you don’t just identify that someone is not going to do well,” Dr. Cohen said, “but that you actually get to act on it and make them do better as a result of that information.”

Future Directions

“Circulating tumor DNA is a good prognostic marker, and it’s emerging as a predictive one,” she concluded. Although not yet a replacement for standard imaging or clinical assessment, ctDNA represents a promising adjunct in adjuvant decision-making, surveillance after treatment, and clinical trial design.

“Circulating tumor DNA is a good prognostic marker, and it’s emerging as a predictive one.”

— STACEY COHEN, MD

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Its integration into routine practice will likely depend on additional prospective data as well as strategies to expand access beyond academic centers. Equity considerations—including assay cost, turnaround time, and laboratory infrastructure—will remain central as oncologists seek to translate precision technologies into broader patient benefit.

DISCLOSURE: Dr. Cohen has served as a consultant and/or served on advisory boards for Agenus, AbbVie, Incyte, Exact Sciences, Guardant Health, Janssen, DoMore Diagnostics, Merck, Roche, Pfizer, Taiho Pharmaceutical, and Regeneron; has received research funding from Natera, Pfizer, Biomea Fusion, BioNTech, and BillionToOne; and served on the independent data monitoring committee for GlaxoSmithKline.

REFERENCES

1. Tie J, Cohen JD, Lahouel K, et al: Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 386:2261-2272, 2022.
2. Lieu CH, Yu G, Kopetz S, et al: NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-North America). 2025 ASCO Gastrointestinal Cancers Symposium. Abstract TPS310. Presented January 25, 2025.
3. Yukami H, Nakamura Y, Mishima S, et al: Circulating tumor DNA dynamics in patients with colorectal cancer with molecular residual disease: Updated analysis from GALAXY study in the CIRCULATE-JAPAN. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 6. Presented January 22, 2024.
4. Kasi PM, Aushev VN, Ensor J, et al: Circulating tumor DNA for informing adjuvant chemotherapy in stage II/III colorectal cancer: Interim analysis of BESPOKE CRC study. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 9. Presented January 22, 2024.
5. Maddalena G, Pellatt AJ, Eluri M, et al: INTERCEPT Program of circulating tumor DNA testing for minimal residual disease in colorectal cancer: Results from a prospective clinical cohort. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract 27. Presented January 20, 2024.